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A 14-year-old girl with no significant past medical history presents to the emergency department for evaluation of 9 days of fever, abdominal pain, and nausea. On day 1 of illness, she was seen at an urgent care with no testing performed and diagnosed with a viral illness. On day 3 of illness, she was evaluated at a different emergency department with negative nasal viral swabs and urinalysis and again diagnosed with viral illness. On day 9 of illness, she continued to have fevers with temperatures as high as 103°F, nausea, and abdominal pain. On the morning of this presentation, she developed a new symptom of pain in her right foot with difficulty ambulating that spontaneously resolved and had a brief episode of word-finding difficulty that lasted approximately 1 hour without any headache, visual disturbances, gait abnormalities, or weakness.On initial examination, she is afebrile with appropriate blood pressure, pulse oximetry, heart rate, and respiratory rate for her age. Her physical examination is significant for moderate distress due to peri-umbilical pain. The remainder of her physical examination is unremarkable.An initial evaluation is performed with complete blood count, comprehensive metabolic panel, inflammatory markers, chest radiograph, and computed tomography (CT) of the abdomen and pelvis. The laboratory evaluations are significant for leukocytosis (white blood count, 28.85 K/uL; 79% neutrophils) and elevated erythrocyte sedimentation rate at 67 mm/h. A chest radiograph shows no acute cardiopulmonary findings. CT of her abdomen shows a wedge-shaped hypodense lesion of the right kidney (Figure 1). With these findings, she is suspected of having acute focal bacterial nephritis (AFBN), which is a bacterial infection of the kidney that causes inflammation in localized areas, often appearing as wedge-shaped lesions on imaging.1 She is started on intravenous ceftriaxone for AFBN, with blood cultures obtained prior to initiation of antibiotics.During her hospitalization, on day 12 of illness, she complains of right calf pain prompting workup for a deep vein thrombosis (DVT). Venous duplex of the bilateral lower extremities shows no evidence of a DVT. Due to the patient’s continued calf pain, magnetic resonance imaging (MRI) of the right lower extremity is obtained that shows an arterial thrombus at the posterior tibial neurovascular bundle. Given the arterial thrombus of the right lower extremity and history of word finding difficulty on initial evaluation, an MRI of the brain is obtained, showing punctate foci restricted diffusion within the bilateral parietal lobes (Figure 2).Based on the patient’s presentation of 9 days of fever, abdominal pain, and nausea, with leukocytosis, neutrophilia, and elevated inflammatory markers, her initial differential diagnoses were focused on intrabdominal infections, and less likely inflammatory or autoimmune conditions. Given the concern for abdominal infections, abdominal CT was obtained and demonstrated AFBN. With the development of further symptoms, and subsequent imaging showing right lower extremity arterial thrombus, with infarcts of the brain and kidney, differential diagnoses were then narrowed to etiologies that could cause arterial thrombi. Her revised differential diagnosis included congenital and acquired hypercoagulable states, infective endocarditis (IE), paradoxical emboli from an intracardiac shunt, atrial myxoma, and vasculitis including Takayasu arteritis.2With evidence of multiorgan arterial infarcts (kidney and brain) and right lower extremity arterial thrombus, an echocardiogram was obtained. The echocardiogram (Figure 3) showed an isolated 3- to 4-cm by 1-cm, pedunculated, irregular shape mass attached to the lateral wall of the left atrium that extends through the mitral valve, with mild-moderate mitral valve regurgitation and stenosis associated with the mass (mean gradient of 6–7 mm Hg across the valve). No other structural abnormalities were visualized, with normal biventricular size and global systolic function.Daily blood cultures obtained from admission failed to grow any pathologic organisms, and cultures of the mass failed to grow any organisms. Metagenomic sequencing DNA testing of the mass identified Haemophilus parainfluenza. Based on the modified Duke criteria (Table 1), the patient met pathologic criteria for endocarditis with microorganism identified in the mass and negative pathology for myxoma. The patient did not meet major criteria with only evidence of endocardial involvement and did not meet minor criteria with only fever and vascular criteria.Pediatric IE is a rare condition, with the incidence estimated to be 0.43 to 0.69 cases per 100 000 child-year.3 The diagnosis of pediatric IE is difficult to make due to nonspecific clinical manifestations, and pediatric IE may be misdiagnosed as more common conditions. The presentation of pediatric IE is highly dependent on the age of the children but commonly presents with fever, fatigue, and a loss of appetite.4 Children can also present with findings secondary to emboli, including renal and cerebral involvement.5Congenital heart disease is the main predisposing condition in pediatric IE, with 50% to 70% of pediatric IE seen in children with congenital heart disease.6 Children with underlying chronic health conditions also have increased risk of pediatric IE, including children whose condition requires central catheters or who gave an immunocompromised state.7 Previously, healthy children make up an approximately 8% to 10%5 of children with IE and in this subset the mitral or aortic valve are the most often affected.4Blood culture-negative pediatric IE accounts for approximately 12% of all pediatric IE. 5 The majority of children with culture-negative pediatric IE received antibiotics prior to culture being obtained, with current indications for collecting blood culture including unexplained fever in patients at risk for IE (such as those with congenital or acquired valvular heart disease, previous IE, prosthetic heart valves, certain congenital or heritable heart malformations, immunodeficiency states, or injection drug use), and the recent onset of left-sided valve regurgitation.8 It is also important to note that appropriate blood culture volume by patient weight and culture bottle type/set (ie, aerobic and anaerobic) are important in maximizing recovery of pathogens. Less common etiologies of culture-negative pediatric IE include cases caused by fastidious growing organisms such as the HACEK organisms (Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella, and Kingella), Coxiella, and Bartonella.5 Diagnosis of culture-negative pediatric IE often relies on a combination of clinical criteria, imaging studies, and molecular techniques for pathogen detection. Effective management of culture-negative pediatric IE requires a high index of suspicion, through clinical evaluation and alternative testing. Given the potential for severe complications, early recognition and appropriate therapy are critical for improving patient outcomes in culture-negative cases.The modified Duke criteria can aid in diagnosis of pediatric IE. Diagnosis of endocarditis can be achieved with pathologic or clinical criteria (Table 1).9 For a definite diagnosis, either pathologic criteria is met, both major clinical criteria are met, or all minor clinical criteria are met. Pathologic criteria include microorganisms in a vegetation or pathologic lesions. Microorganisms in a vegetation can be demonstrated by culture or histologic examination of vegetation, and pathologic lesion can be demonstrated by histologic examination. The 2 major clinical criteria include blood cultures positive for endocarditis and evidence of endocardial involvement. Evidence of endocardial involvement can be demonstrated by echocardiogram, CT, or MRI. The 5 minor criteria include predisposing heart condition, fever, vascular phenomena, immunologic phenomena, and microbiological evidence that do not fit the major criteria.9As illustrated in this case, cell-free DNA (cfDNA) allows testing for organisms where cultures are negative or fastidious organisms are involved.10 By analyzing cfDNA extracted from a blood sample, clinicians can rapidly obtain pathogen results with a noninvasive test, allowing for timely initiation of antimicrobial therapy. In some other diseases, cfDNA serves as a biomarker for disease severity and treatment response, enabling clinicians to monitor effectiveness of therapy.11 The most recent modified Duke criteria has included metagenomic sequencing as a diagnostic tool for identification of a microorganism.Management of IE involves a combination of antimicrobial therapy and, in some cases, surgical intervention. Antimicrobial regimens are selected based on the causative microorganism. The 2015 American Heart Association guidelines5 provide management recommendations for pediatric IE. Bactericidal antibiotics are preferred over bacteriostatic given treatment failure and relapse risk (Class I; Level of Evidence A), intravenous antibiotics are recommended over intramuscular given small muscle mass in infants and children (Class I; Level of Evidence C), and a prolonged course of therapy, typically 4 to 6 weeks, is advised (Class I; Level of Evidence B). Surgical intervention is sometimes required to manage infection and sequelae of valve and tissue destruction. The 2015 European Society of Cardiology (ESC) guidelines12 provide indications for surgery of IE. Indications include heart failure due to valvular dysfunction, uncontrolled infection with persistent bacteremia despite appropriate therapy, and prevention of systemic embolization, especially if there have been previous embolic events.Long-term management of postoperative and adequately treated pediatric IE, subacute bacterial endocarditis (SBE) prophylaxis must be implemented after conclusion of acute treatment. Prophylaxis is particularly important for patients with preexisting heart conditions, such as history of IE, history of prosthetic heart valve or prosthetic material used for repair, certain congenital heart disease, or heart transplant recipients with valvular disease. Administering antibiotics prior to certain invasive procedures can reduce the risk of bacterial infection in the bloodstream and subsequent colonization of the heart valves. Typical antibiotic prophylaxis is amoxicillin 50 mg/kg one dose 30 to 60 minutes prior to procedure. Alternatively, doxycycline (2.2 mg/kg) or azithromycin (15 mg/kg) is recommended for penicillin allergic patients. Additionally, all patients requiring SBE prophylaxis require regular dental hygiene and dental examinations to help prevent IE. 13Based on the 2015 ESC guidelines for surgery of IE, surgery was indicated given the patient had valve dysfunction, systemic embolization, large mobile vegetation despite antibiotic therapy, and neurologic complications.12 The intracardiac mass (Figure 4) on the mitral valve was successfully removed and mitral valve was repaired. The patient was treated with a total duration of 4-week course of both ceftriaxone and anticoagulation, which was completed outpatient. Echocardiogram at discharge showed only trace mitral regurgitation (MR) and no stenosis. At her 1-month follow-up, repeat echocardiogram showed only trivial MR and well-functioning mitral valve. Additionally, she had a repeat leg doppler with no evidence of thrombosis and abdominal ultrasonogram with no evidence of renal infarct. Remarkably, this patient has returned to all activities, with no chronic cardiac injury, kidney injury, and with normal neurologic status. The patient will require SBE prophylaxis indefinitely, but no other adaptations.Infective endocarditis (IE) is a rare occurrence, especially in children with structurally normal hearts.5Culture-negative pediatric IE occurs rarely with most cases being secondary to antibiotic use prior to culture collection.5Most recent revisions to the modified Duke criteria include alternative methods of identifying microorganism, including metagenomic sequencing, to aid in identification of the causative microorganism.Given variability in presentation of pediatric IE, a high index of suspicion must be retained for patients with infection of unknown origin and systemic emboli, even in the setting of children with structurally normal hearts and negative cultures.